The present invention is in the field of medicinal chemistry and relates to pyrazole compounds that are protein kinase inhibitors, especially inhibitors of ERK, compositions containing such compounds and methods of use. The compounds are useful for treating cancer and other diseases that are alleviated by protein kinase inhibitors.
Mammalian mitogen-activated protein (MAP)1 kinases are serine/threonine kinases that mediate intracellular signal transduction pathways (Cobb and Goldsmith, 1995, J Biol. Chem., 270, 14843; Davis, 1995, Mol. Reprod. Dev. 42, 459). Members of the MAP kinase family share sequence similarity and conserved structural domains, and include the ERK2 (extracellular signal regulated kinase), JNK (Jun N-terminal kinase), and p38 kinases. JNKs and p38 kinases are activated in response to the pro-inflammatory cytokines TNF-alpha and interleukin-1, and by cellular stress such as heat shock, hyperosmolarity, ultraviolet radiation, lipopolysaccharides and inhibitors of protein synthesis (Derijard et al., 1994, Cell 76, 1025; Han et al., 1994, Science 265, 808; Raingeaud et al., 1995, J Biol. Chem. 270, 7420; Shapiro and Dinarello, 1995, Proc. Natl. Acad. Sci. USA 92, 12230). In contrast, ERKs are activated by mitogens and growth factors (Bokemeyer et al. 1996, Kidney Int. 49, 1187).
ERK2 is a widely distributed protein kinase that achieves maximum activity when both Thr183 and Tyr185 are phosphorylated by the upstream MAP kinase kinase, MEK1 (Anderson et al., 1990, Nature 343, 651; Crews et al., 1992, Science 258, 478). Upon activation, ERK2 phosphorylates many regulatory proteins, including the protein kinases Rsk90 (Bjorbaek et al., 1995, J. Biol. Chem. 270, 18848) and MAPKAP2 (Rouse et al., 1994, Cell 78, 1027), and transcription factors such as ATF2 (Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247), Elk-1 (Raingeaud et al. 1996), c-Fos (Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952), and c-Myc (Oliver et al., 1995, Proc. Soc. Exp. Biol. Med. 210, 162). ERK2 is also a downstream target of the Ras/Raf dependent pathways (Moodie et al., 1993, Science 260, 1658) and may help relay the signals from these potentially oncogenic proteins. ERK2 has been shown to play a role in the negative growth control of breast cancer cells (Frey and Mulder, 1997, Cancer Res. 57, 628) and hyperexpression of ERK2 in human breast cancer has been reported (Sivaraman et al., 1997, J Clin. Invest. 99, 1478). Activated ERK2 has also been implicated in the proliferation of endothelin-stimulated airway smooth muscle cells, suggesting a role for this kinase in asthma (Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol. 16, 589).
Aurora-2 is a serine/threonine protein kinase that has been implicated in human cancer, such as colon, breast and other solid tumors. This kinase is believed to be involved in protein phosphorylation events that regulate the cell cycle. Specifically, Aurora-2 may play a role in controlling the accurate segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities. In human colon cancer tissue, the aurora-2 protein has been found to be overexpressed. See Bischoff et al., EMBO J., 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771.
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of xcex1 and xcex2 isoforms that are each encoded by distinct genes [Coghlan et al., Chemistry and Biology, 7, 793-803 (2000); Kim and Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK-3 has been implicated in various diseases including diabetes, Alzheimer""s disease, CNS disorders such as manic depressive disorder and neurodegenerative diseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; and Haq et al., J. Cell Biol. (2000) 151, 117]. These diseases may be caused by, or result in, the abnormal operation of certain cell signaling pathways in which GSK-3 plays a role. GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins. These proteins include glycogen synthase which is the rate limiting enzyme necessary for glycogen synthesis, the microtubule associated protein Tau, the gene transcription factor xcex2-catenin, the translation initiation factor e1F2B, as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBxcex1. These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development.
In a GSK-3 mediated pathway that is relevant for the treatment of type II diabetes, insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. Along this pathway, GSK-3 is a negative regulator of the insulin-induced signal. Normally, the presence of insulin causes inhibition of GSK-3 mediated phosphorylation and deactivation of glycogen synthase. The inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93, 8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J. 299, 123-128 (1994)]. However, in a diabetic patient where the insulin response is impaired, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood levels of insulin. This leads to abnormally high blood levels of glucose with acute and long term effects that may ultimately result in cardiovascular disease, renal failure and blindness. In such patients, the normal insulin-induced inhibition of GSK-3 fails to occur. It has also been reported that in patients with type II diabetes, GSK-3 is overexpressed [WO 00/38675]. Therapeutic inhibitors of GSK-3 therefore are considered to be useful for treating diabetic patients suffering from an impaired response to insulin.
GSK-3 activity has also been associated with Alzheimer""s disease. This disease is characterized by the well-known xcex2-amyloid peptide and the formation of intracellular neurofibrillary tangles. The neurofibrillary tangles contain hyperphosphorylated Tau protein where Tau is phosphorylated on abnormal sites. GSK-3 has been shown to phosphorylate these abnormal sites in cell and animal models. Furthermore, inhibition of GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells [Lovestone et al., Current Biology 4, 1077-86 (1994); Brownlees et al., Neuroreport 8, 3251-55 (1997)]. Therefore, it is believed that GSK-3 activity may promote generation of the neurofibrillary tangles and the progression of Alzheimer""s disease.
Another substrate of GSK-3 is xcex2-catenin which is degradated after phosphorylation by GSK-3. Reduced levels of xcex2-catenin have been reported in schizophrenic patients and have also been associated with other diseases related to increase in neuronal cell death [Zhong et al., Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993); Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997)].
As a result of the biological importance of GSK-3, there is current interest in therapeutically effective GSK-3 inhbitors. Small molecules that inhibit GSK-3 have recently been reported [WO 99/65897 (Chiron) and WO 00/38675 (SmithKline Beecham)].
Aryl substituted pyrroles are known in the literature. In particular, tri-aryl pyrroles (U.S. Pat. No. 5,837,719) have been described as having glucagon antagonist activity. 1,5-Diarylpyrazoles have been described as p38 inhibitors (WO 9958523).
There is a high unmet medical need to develop new therapeutic treatments that are useful in treating the various conditions associated with ERK2 activation. For many of these conditions the currently available treatment options are inadequate.
Accordingly, there is great interest in new and effective inhibitors of protein kinase, including ERK2 inhibitors, that are useful in treating various conditions associated with protein kinase activation.
It has now been found that compounds of this invention and compositions thereof are effective as protein kinase inhibitors, especially as inhibitors of ERK2. These compounds have the general formula I: 
or a pharmaceutically acceptable derivative thereof, wherein:
Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and QR2 are attached to Sp at non-adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6;
Z1 and Z2 are each independently selected from N or CH;
T and Q are each an independently selected linker group;
U is selected from xe2x80x94NR7xe2x80x94, xe2x80x94NR7COxe2x80x94, xe2x80x94NR7CONR7xe2x80x94, xe2x80x94NR7CO2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CONR7xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94NR7SO2xe2x80x94, xe2x80x94SO2NR7xe2x80x94, xe2x80x94NR7SO2NR7xe2x80x94, or xe2x80x94SO2xe2x80x94;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH;
R2 is selected from xe2x80x94(CH2)yR5, xe2x80x94(CH2)yCH(R5)2, xe2x80x94(CH2)yCH(R8)CH(R5)2, xe2x80x94N(R4)2, or xe2x80x94NR4(CH2)yN(R4)2;
y is 0-6;
R3 is selected from R7, R, xe2x80x94(CH2)yCH(R8)R, CN, xe2x80x94(CH2)yCH(R8)CH(R5)2, or xe2x80x94(CH2)yCH(R8)N(R4)2;
each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms;
each R4 is independently selected from R, R7, xe2x80x94COR7, xe2x80x94CO2R, xe2x80x94CON(R7)2, xe2x80x94SO2R7, xe2x80x94(CH2)yR5, or xe2x80x94(CH2)yCH(R5)2;
each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring;
R8 is selected from R, (CH2)wOR7, (CH2)wN(R4)2, or (CH2)wSR7; and
each w is independently selected from 0-4.
As used herein, the following definitions shall apply unless otherwise indicated. The phrase xe2x80x9coptionally substitutedxe2x80x9d is used interchangeably with the phrase xe2x80x9csubstituted or unsubstitutedxe2x80x9d or with the term xe2x80x9c(un)substituted.xe2x80x9d Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.
The term xe2x80x9caliphaticxe2x80x9d or xe2x80x9caliphatic groupxe2x80x9d as used herein means a straight-chain or branched C1-C12 hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic C3-C8 hydrocarbon or bicyclic C8-C12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccycloalkylxe2x80x9d), that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members. For example, suitable aliphatic groups include, but are not limited to, linear or branched or alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
The terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkoxyxe2x80x9d, xe2x80x9chydroxyalkylxe2x80x9d, xe2x80x9calkoxyalkylxe2x80x9d, and xe2x80x9calkoxycarbonylxe2x80x9d, used alone or as part of a larger moiety includes both straight and branched chains containing one to twelve carbon atoms. The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d used alone or as part of a larger moiety shall include both straight and branched chains containing two to twelve carbon atoms.
The terms xe2x80x9chaloalkylxe2x80x9d, xe2x80x9chaloalkenylxe2x80x9d and xe2x80x9chaloalkoxyxe2x80x9d means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term xe2x80x9chalogenxe2x80x9d means F, Cl, Br, or I.
The term xe2x80x9cheteroatomxe2x80x9d means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. Also the term xe2x80x9cnitrogenxe2x80x9d includes a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl).
The term xe2x80x9carylxe2x80x9d used alone or as part of a larger moiety as in xe2x80x9caralkylxe2x80x9d, xe2x80x9caralkoxyxe2x80x9d, or xe2x80x9caryloxyalkylxe2x80x9d, refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term xe2x80x9carylxe2x80x9d may be used interchangeably with the term xe2x80x9caryl ringxe2x80x9d.
The term xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclylxe2x80x9d, or xe2x80x9cheterocyclicxe2x80x9d as used herein means non-aromatic, monocyclic, bicyclic or tricyclic ring systems having five to fourteen ring members in which one or more ring members is a heteroatom, wherein each ring in the system contains 3 to 7 ring members.
The term xe2x80x9cheteroarylxe2x80x9d, used alone or as part of a larger moiety as in xe2x80x9cheteroaralkylxe2x80x9d or xe2x80x9cheteroarylalkoxyxe2x80x9d, refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term xe2x80x9cheteroarylxe2x80x9d may be used interchangeably with the term xe2x80x9cheteroaryl ringxe2x80x9d or the term xe2x80x9cheteroaromaticxe2x80x9d.
An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group are selected from halogen, xe2x80x94R0, xe2x80x94OR0, xe2x80x94SR0, 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph), Ph substituted with R0, xe2x80x94O(Ph), Oxe2x80x94(Ph) substituted with R0, xe2x80x94CH2(Ph), xe2x80x94CH2(Ph) substituted with R0, xe2x80x94CH2CH2(Ph), xe2x80x94CH2CH2(Ph) substituted with R0, xe2x80x94NO2, xe2x80x94CN, xe2x80x94N(R0)2, xe2x80x94NR0C(O)R0, xe2x80x94NR0C(O)N(R0)2, xe2x80x94NR0CO2R0, xe2x80x94HR0NR0xe2x80x94C(O)R0, xe2x80x94NR0NR0C(O)N(R0)2, xe2x80x94NR0NR0CO2R0, xe2x80x94C(O)C(O)R0, xe2x80x94C(O)CH2C(O)R0, xe2x80x94CO2R0, xe2x80x94C(O)R0, xe2x80x94C(O)N(R0)2, xe2x80x94OC(O)N(R0)2, xe2x80x94S(O)2R0, xe2x80x94SO2N(R0)2, xe2x80x94S(O)R0, xe2x80x94NR0SO2N(R0)2, xe2x80x94NR0SO2R0, xe2x80x94C(xe2x95x90S)N(R0)2, xe2x80x94C(xe2x95x90NH)xe2x80x94N(R0)2, xe2x80x94(CH2)yNHC(O)R0, or xe2x80x94(CH2)yNHC(O)CH(Vxe2x80x94R0)(R0), wherein each R0 is independently selected from hydrogen, optionally substituted C1-6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl (Ph), xe2x80x94O(Ph), or xe2x80x94CH2(Ph)xe2x80x94CH2(Ph), wherein y is 0-6; and V is a linker group. Substituents on the aliphatic group of R0 are selected from NH2, NH(C1-4 aliphatic), N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, OH, Oxe2x80x94(C1-4 aliphatic), NO2, CN, CO2H, CO2(C1-4 aliphatic), xe2x80x94O(halo C1-4 aliphatic), or halo C1-4 aliphatic.
An aliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and the following: xe2x95x90O, xe2x95x90S, xe2x95x90NNHR*, xe2x95x90NN(R*)2, xe2x95x90Nxe2x80x94, xe2x95x90NNHC(O)R*, xe2x95x90NNHCO2(alkyl), xe2x95x90NNHSO2(alkyl), or xe2x95x90NR*, where each R* is independently selected from hydrogen or an optionally substituted C1-6 aliphatic. Substituents on the aliphatic group of R* are selected from NH2, NH(C1-4 aliphatic), N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, OH, Oxe2x80x94(C1-4 aliphatic), NO2, CN, CO2H, CO2(C1-4 aliphatic), xe2x80x94C(halo C1-4 aliphatic), or halo C1-4 aliphatic.
Substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from xe2x80x94R+, xe2x80x94N(R+)2, xe2x80x94C(O)R+, xe2x80x94CO2R+, xe2x80x94C(O)C(O)R+, xe2x80x94C(O)CH2C(O)R+, xe2x80x94SO2R+, xe2x80x94SO2N(R+)2, xe2x80x94C(xe2x95x90S)N(R+)2, xe2x80x94C(xe2x95x90NH)xe2x80x94N(R+)2, or xe2x80x94NR+SO2R+; wherein R+is hydrogen, an optionally substituted C1-6 aliphatic, optionally substituted phenyl (Ph), optionally substituted xe2x80x94O(Ph), optionally substituted xe2x80x94CH2(Ph), optionally substituted xe2x80x94CH2CH2(Ph), or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring. Substituents on the aliphatic group or the phenyl ring of R+are selected from NH2, NH(C1-4 aliphatic), N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, OH, Oxe2x80x94(C1-4 aliphatic), NO2, CN, CO2H, CO2(C1-4 aliphatic), xe2x80x94O(halo C1-4 aliphatic), or halo C1-4 aliphatic.
The term xe2x80x9calkylidene chainxe2x80x9d refers to an optionally substituted, straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation. The optional substituents are as described above for an aliphatic group.
The term xe2x80x9cspacer groupxe2x80x9d refers to a group that separates and orients other parts of the molecule attached thereto, such that the compound favorably interacts with functional groups in the active site of an enzyme. As used herein, the spacer group separates and orients ring A and QR2 within the active site such that they may form favorable interactions with functional groups which exist within the active site of the ERK2 enzyme. When the spacer group is a 5-membered heteroaromatic ring, ring A and QR2 are attached at non-adjacent positions xe2x80x9cBxe2x80x9d and xe2x80x9cCxe2x80x9d, and the 5-membered ring is attached to ring A at point xe2x80x9cDxe2x80x9d and to QR2 at point xe2x80x9cExe2x80x9d as illustrated below. 
Preferably, the distance between xe2x80x9cDxe2x80x9d and xe2x80x9cCxe2x80x9d is 3.77 xc3x85, the distance between xe2x80x9cDxe2x80x9d and xe2x80x9cExe2x80x9d is 5.0 xc3x85, the distance between xe2x80x9cBxe2x80x9d and xe2x80x9cCxe2x80x9d is 2.2 xc3x85, and the distance between xe2x80x9cBxe2x80x9d and xe2x80x9cExe2x80x9d is 3.5 xc3x85, wherein each of the above described distances is plus/minus 0.2 xc3x85.
The spacer group itself may also form additional interactions within the active site to further enhance inhibitory activity of the compounds. For example, when Sp is a pyrrole the pyrrole-NH may form an additional hydrogen bond within the active site of the ERK2 enzyme.
The term xe2x80x9clinker groupxe2x80x9d means an organic moiety that connects two parts of a compound. Linkers are typically comprised of an atom such as oxygen or sulfur, a unit such as xe2x80x94NHxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94, or a chain of atoms, such as an alkylidene chain. The molecular mass of a linker is typically in the range of about 14 to 200. Examples of linkers include a saturated or unsaturated C1-6 alkylidene chain which is optionally substituted, and wherein up to two saturated carbons of the chain are optionally replaced by xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)C(O)xe2x80x94, xe2x80x94CONR7xe2x80x94, xe2x80x94CONR7NR7xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94NR7CO2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NR7CONR7xe2x80x94, xe2x80x94OC(O)NR7xe2x80x94, xe2x80x94NR7NR7xe2x80x94, xe2x80x94NR7COxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR7 xe2x80x94SO2NR7xe2x80x94, or xe2x80x94NR7SO2xe2x80x94.
As used herein, linker group Q connects Sp with R2. Q may also form additional interactions within the ERK2 binding site to further enhance the inhibitory activity of the compound. When Q is a carbonyl-containing moeity such as xe2x80x94C(O)xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)C(O)xe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94CO2NHxe2x80x94, xe2x80x94CONHNHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94OC(O)NHxe2x80x94, or xe2x80x94NHCO2xe2x80x94, or a sulfonyl-containing moeity such as xe2x80x94SO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, or xe2x80x94NHSO2xe2x80x94, the carbonyl or sulfonyl oxygen forms a hydrogen-bond with lysine 54 in the ERK2 binding site. When Q is an NH-containing moeity such as xe2x80x94CH2NHxe2x80x94 or xe2x80x94NHNHxe2x80x94, the NH-group forms a hydrogen-bond with aspartic acid residue 167 in the ERK2 binding site. When Q is a hydrophobic group such as an alkyl chain, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94, Q forms additional hydrophobic interactions within the ERK2 binding site.
R2 forms hydrophobic interactions within the binding site of ERK2, especially with the side-chain carbons of lysine 54 and aspartic acid 167. R2 may also form hydrophobic interactions with the glycine-rich loop which is made up of amino-acid residues 33-38. When R2 is substituted, the substituents may form further interactions within the binding site to enhance the inhibitory activity of the compound. For example, when a substituent on R2 is a hydrogen-bond donor or a hydrogen-bond acceptor, said substituent forms a hydrogen bond with enzyme-bound water molecules that exist in the binding site.
As used herein, linker group T, when present, connects Sp with R1. T may also form additional interactions within the ERK2 binding site to further enhance the inhibitory activity of the compound. When T is carbonyl-containing such as xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94COCOxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94CO2NHxe2x80x94, xe2x80x94CONHNHxe2x80x94, xe2x80x94NHCOxe2x80x94, or xe2x80x94NHCO2xe2x80x94, or sulfonyl-containing such as xe2x80x94SO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, or xe2x80x94NHSO2xe2x80x94, the carbonyl or sulfonyl oxygen forms a hydrogen-bond with the NH of glutamine 105 in the ERK2 binding site. When T is NH-containing such as xe2x80x94CH2NHxe2x80x94 or xe2x80x94NHNHxe2x80x94, the NHxe2x80x94group forms a hydrogen-bond with the carbonyl of glutamine 105. When T is a hydrophobic group such as an alkyl chain, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94, T forms additional hydrophobic interactions with the side-chain carbons of glutamine 105 as well as isoleucine 84.
The binding interactions described herein between the compounds of this invention and the ERK2 binding site have been determined by molecular modeling programs that are known to those of ordinary skill in the art. These molecular modeling programs include QUANTA [Molecular Simulations, Inc., Burlington, Mass., 1992] and SYBYL [Molecular Modeling Software, Tripos Associates, Inc., St. Louis, Mo., 1992]. As used herein, the amino acid numbering for the ERK2 enzyme corresponds to the Swiss-Prot database entry for accession #P28482. The Swiss-Prot database is an international protein sequence database distributed by the European Bioinformatics Institute (EBI) in Geneva, Switzerland. The database can be found at www.ebi.ac.uk/swissprot.
The compounds of this invention are limited to those that are chemically feasible and stable. Therefore, a combination of substituents or variables in the compounds described above is permissible only if such a combination results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature of 40xc2x0 C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention.
Compounds of formula I or salts thereof may be formulated into compositions. In a preferred embodiment, the composition is a pharmaceutically acceptable composition. In one embodiment, the composition comprises an amount of the protein kinase inhibitor effective to inhibit a protein kinase, particularly ERK-2, in a biological sample or in a patient. In another embodiment, compounds of this invention and pharmaceutical compositions thereof, which comprise an amount of the protein kinase inhibitor effective to treat or prevent an ERK-2-mediated condition and a pharmaceutically acceptable carrier, adjuvant, or vehicle, may be formulated for administration to a patient.
The term xe2x80x9cpatientxe2x80x9d includes human and veterinary subjects.
The term xe2x80x9cbiological samplexe2x80x9d, as used herein, includes, without limitation, cell cultures or extracts thereof; preparations of an enzyme suitable for in vitro assay; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
Another aspect of this invention relates to a method of treating or preventing an ERK-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable comprising said compound.
The term xe2x80x9cERK-2-mediated conditionxe2x80x9d or xe2x80x9cdiseasexe2x80x9d, as used herein, means any disease or other deleterious condition in which ERK-2 is known to play a role. The term xe2x80x9cERK-2-mediated conditionxe2x80x9d or xe2x80x9cdiseasexe2x80x9d also means those diseases or conditions that are alleviated by treatment with an ERK-2 inhibitor. Such conditions include, without limitation, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, Alzheimer""s disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders and hormone-related diseases. The term xe2x80x9ccancerxe2x80x9d includes, but is not limited to the following cancers: breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin""s, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, and leukemia.
The present method is especially useful for treating a disease that is alleviated by the use of an inhibitor of ERK2 or other protein kinases. Although the present compounds were designed as ERK2 inhibitors, it has been found that certain compounds of this invention also inhibit other protein kinases such as GSK3, Aurora2, Lck, CDK2, and AKT3.
Another aspect of the invention relates to inhibiting ERK-2 activity in a biological sample, which method comprises contacting the biological sample with a compound of formula I, or a pharmaceutically acceptable composition comprising said compound.
Another aspect of this invention relates to a method of inhibiting ERK-2 activity in a patient, which method comprises administering to the patient a compound of formula I or a pharmaceutically acceptable composition comprising said compound.
Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable comprising said compound.
The term xe2x80x9cAurora-2-mediated conditionxe2x80x9d or xe2x80x9cdiseasexe2x80x9d, as used herein, means any disease or other deleterious condition in which Aurora is known to play a role. The term xe2x80x9cAurora-2-mediated conditionxe2x80x9d or xe2x80x9cdiseasexe2x80x9d also means those diseases or conditions that are alleviated by treatment with an Aurora-2 inhibitor. Such conditions include, without limitation, cancer. The term xe2x80x9ccancerxe2x80x9d includes, but is not limited to the following cancers: colon, breast, stomach, and ovarian.
Another aspect of the invention relates to inhibiting Aurora-2 activity in a biological sample, which method comprises contacting the biological sample with a compound of formula I, or a pharmaceutically acceptable composition comprising said compound.
Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula I or a pharmaceutically acceptable composition comprising said compound.
Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable comprising said compound.
The term xe2x80x9cGSK-3-mediated conditionxe2x80x9d or xe2x80x9cdiseasexe2x80x9d, as used herein, means any disease or other deleterious condition or state in which GSK-3 is known to play a role. Such diseases or conditions include, without limitation, diabetes, Alzheimer""s disease, Huntington""s Disease, Parkinson""s Disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiomycete hypertrophy, reperfusion/ischemia, and baldness.
One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer""s disease. Another method relates to inhibiting the phosphorylation of xcex2-catenin, which is useful for treating schizophrenia.
Another aspect of the invention relates to inhibiting GSK-3 activity in a biological sample, which method comprises contacting the biological sample with a compound of formula I.
Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula I or a pharmaceutically acceptable composition comprising said compound.
Inhibition of ERK2, Aurora2, CDK2, GSK-3, Lck, or AKT3 kinase activity in a biological sample is useful for a variety of purposes which are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-translplantation, biological specimen storage, and biological assays.
The term xe2x80x9cpharmaceutically acceptable carrier, adjuvant, or vehiclexe2x80x9d refers to a non-toxic carrier, adjuvant, or vehicle that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof.
The amount effective to inhibit protein kinase, for example, Aurora-2 and GSK-3, is one that measurably inhibits the kinase activity where compared to the activity of the enzyme in the absence of an inhibitor. Any method may be used to determine inhibition, such as, for example, the Biological Testing Examples described below.
Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term xe2x80x9cparenteralxe2x80x9d as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.
Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
In addition to the compounds of this invention, pharmaceutically acceptable derivatives of the compounds of this invention may also be employed in compositions to treat or prevent the above-identified diseases or disorders.
A xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. Particularly favored derivatives are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N+(C1-4 alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
The amount of the protein kinase inhibitor that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of the inhibitor will also depend upon the particular compound in the composition.
The kinase inhibitors of this invention or pharmaceutical compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Implantable devices coated with a kinase inhibitor of this invention are another embodiment of the present invention.
Depending upon the particular protein kinase-mediated condition to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention. For example, in the treatment of cancer other chemotherapeutic agents or other anti-proliferative agents may be combined with the protein kinase inhibitors of this invention to treat cancer. These agents include, without limitation, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives.
Other examples of agents the inhibitors of this invention may also be combined with include, without limitation, agents for treating diabetes such as insulin or insulin analogues, in injectable or inhalation form, glitazones, alpha glucosidase inhibitors, biguanides, insulin sensitizers, and sulfonyl ureas; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.
Those additional agents may be administered separately from the protein kinase inhibitor-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the protein kinase inhibitor of this invention in a single composition.
Compounds of this invention may exist in alternative tautomeric forms. Unless otherwise indicated, the representation of either tautomer is meant to include the other.
Accordingly, the present invention relates to compounds of formula I wherein Ring A is a pyridine (II), pyrimidine (III), or triazine (IV) ring as shown below: 
or a pharmaceutically acceptable derivative thereof, wherein Sp, TmR1, R2, UnR3, Q, and T are as described above.
Examples of suitable Sp groups of formula I include pyrrole (a), imidazole (b), pyrazole (c), triazole (d), oxazole (e), isoxazole (f), 1,3-thiazole (g), 1,2-thiazole (h), furan (i), and thiophene (j), as shown below: 
wherein each of a through j is optionally substituted with R6.
Preferred TmR1 groups of formula I are selected from hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R71 halo, nitro, alkoxy, and amino. Preferred TmR1 groups are methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of formula I are those listed in Table 1 below.
Preferred R3 groups of formula I are hydrogen, carbocyclyl, xe2x80x94CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is xe2x80x94CH(R8)R, examples of such groups include xe2x80x94CH(CH2OH)phenyl, xe2x80x94CH(CH2OH)ethyl, xe2x80x94CH(CH2OH)2, xe2x80x94CH(CH2OH) isopropyl, and xe2x80x94CH(CH2OH)CH2cyclopropyl. Preferred Un groups, when present, are xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NR7xe2x80x94, xe2x80x94NHCOxe2x80x94, and xe2x80x94NHCO2xe2x80x94. More preferred UnR3 groups of formula I are those listed in Table 1 below.
When R2 is R5, preferred R5 groups are pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, and piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl, 4-phenyl-piperazine-1-yl, wherein each group is optionally substituted. When R2 is (CH2)yR5, (CH2)yCH(R5)2, or xe2x80x94N(R4)2, preferred R5 groups are further selected from pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl, 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, benzyl, xe2x80x94CH2OH, xe2x80x94(CH2)2OH, and isopropyl, wherein each group is optionally substituted. Preferred substituents on R5 are xe2x80x94OH, pyridyl, piperidinyl, and optionally substituted phenyl. When R2 is xe2x80x94(CH2)yCH(R8)CH(R5)2, preferred R8 groups are R7 and OR7 such as OH and CH2OH and preferred R5 are as described above. Preferred xe2x80x94(CH2)yCH(R8)CH(R5)2 groups of formula I are xe2x80x94CH(OH)CH(OH)phenyl and xe2x80x94CH(Me)CH(OH)phenyl. Other preferred xe2x80x94QR2 groups are those listed in Table 1 below.
Preferred compounds of formula I are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, xe2x80x94CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;
(b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring;
(c) Q is xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94OC(O)NHxe2x80x94, xe2x80x94C(O)ONHxe2x80x94, or xe2x80x94CONHNHxe2x80x94;
(d) R2 is xe2x80x94NR4(CH2)yN(R4)2, xe2x80x94(CH2)yR5, xe2x80x94(CH2)yCH(R5)2, or xe2x80x94(CH2)yCH(R8)CH(R5)2;
(f) R4 is R, R7, or xe2x80x94(CH2)yCH(R5)2; and
(g) R5 is an optionally substituted group selected from C1-6 aliphatic, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl.
More preferred compounds of formula I are those having one or more, more preferably more than one, or most preferably all, of the features selected from the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, xe2x80x94CH(CH2OH)phenyl, xe2x80x94CH(CH2OH)ethyl, xe2x80x94CH(CH2OH)2, xe2x80x94CH(CH2OH)isopropyl, xe2x80x94CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group;
(b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3;
(c) Q is xe2x80x94COxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94SO2xe2x80x94, or xe2x80x94SO2NHxe2x80x94;
(d) R2 is xe2x80x94(CH2)yR5, xe2x80x94(CH2)yCH(R5)21 or xe2x80x94(CH2)yCH(R8)CH(R5)2, wherein R8 is OH or CH2OH; and
(e) R5 is xe2x80x94CH2OH, xe2x80x94(CH2)2OH, isopropyl, or an optionally substituted group selected from pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl, 4-phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl, 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, or benzyl.
A preferred embodiment of this invention relates to compounds of formula Ixe2x80x2: 
or a pharmaceutically acceptable derivative thereof, wherein:
Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and Qxe2x80x2R2 are attached to Sp at non-adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6;
Z1 and Z2 are each independently selected from N or CH;
Qxe2x80x2 is selected from xe2x80x94CO2xe2x80x94, xe2x80x94C(O)NR7xe2x80x94 or xe2x80x94SO2NR7xe2x80x94;
T is a linker group;
U is selected from xe2x80x94NR7xe2x80x94, xe2x80x94NR7COxe2x80x94, xe2x80x94NR7CONR7xe2x80x94, xe2x80x94NR7CO2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CONR7xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94NR7SO2xe2x80x94, xe2x80x94SO2NR7xe2x80x94, xe2x80x94NR7SO2NR7xe2x80x94, or xe2x80x94SO2xe2x80x94;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH;
R2xe2x80x2 is selected from xe2x80x94(CH2)yCH(R5)2 or xe2x80x94(CH2)yCH(R8)CH(R5)2;
y is 0-6;
R3 is selected from R7, R, xe2x80x94(CH2)yCH(R8)R, CN, xe2x80x94(CH2)yCH(R8)CH(R5)2, or xe2x80x94(CH2)yCH(R8)N(R4)2;
each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms;
each R4 is independently selected from R, R7, xe2x80x94COR71, xe2x80x94CO2R, xe2x80x94CON(R7)2, xe2x80x94SO2R7, xe2x80x94(CH2)yR5, or xe2x80x94(CH2)yCH(R5)2;
each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring;
R8 is selected from R, (CH2)wOR7, (CH2)wN(R4)2, or (CH2)wSR7; and
each w is independently selected from 0-4.
Examples of suitable Sp groups of formula Ixe2x80x2 include pyrrole (a), imidazole (b), pyrazole (c), triazole (d), oxazole (e), isoxazole (f), 1,3-thiazole (g), 1,2-thiazole (h), furan (i), and thiophene (j), as shown below: 
wherein each of a through j is optionally substituted with R6.
Accordingly, the present invention relates to compounds of formula Ixe2x80x2 wherein Ring A is a pyridine (IIxe2x80x2), pyrimidine (IIIxe2x80x2), or triazine (IVxe2x80x2) ring as shown below: 
or a pharmaceutically acceptable derivative thereof, wherein Sp, TmR1, Qxe2x80x2R2xe2x80x2, and UnR3 are as described above.
Preferred R5 groups of formula Ixe2x80x2 are R or OR7. Examples of such groups include OH, CH2OH, carbocyclic, or optionally substituted 5 or 6-membered aryl or heteroaryl rings, such as phenyl, pyridyl, and cyclohexyl. Preferred R8 groups of formula Ixe2x80x2 are R and OR7, wherein R is an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include phenyl, methyl, ethyl, OH, and CH2OH. Preferred substituents on the R5 aryl or heteroaryl ring are halogen, haloalkyl, OR0, and R0.
Preferred TmR1 groups of formula Ixe2x80x2 are hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. Preferred TmR1 groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of formula Ixe2x80x2 are those listed in Table 1 below.
Preferred R3 groups of formula Ixe2x80x2 are hydrogen, carbocyclyl, xe2x80x94CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is xe2x80x94CH(R8)R, examples of such groups include xe2x80x94CH(CH2OH)phenyl, xe2x80x94CH(CH2OH)ethyl, xe2x80x94CH(CH2OH)2, xe2x80x94CH(CH2OH)isopropyl, and xe2x80x94CH(CH2OH)CH2cyclopropyl. Preferred Un groups, when present, are xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NR7xe2x80x94, xe2x80x94NHCOxe2x80x94, and xe2x80x94NHCO2xe2x80x94. More preferred UnR3 groups of formula Ixe2x80x2 are those listed in Table 1 below.
Preferred compounds of formula Ixe2x80x2 are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, xe2x80x94CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;
(b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and
(c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted 5 or 6-membered aryl or heteroaryl ring.
More preferred compounds of formula Ixe2x80x2 are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, xe2x80x94CH(CH2OH)phenyl, xe2x80x94CH(CH2OH)ethyl, xe2x80x94CH(CH2OH)2, xe2x80x94CH(CH2OH)isopropyl, xe2x80x94CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group;
(b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3; and
(c) R5 is OH, CH2OH, carbocyclic, or an optionally substituted phenyl or pyridyl ring, and Qxe2x80x2 is C(O)NH.
Another preferred embodiment of this invention relates to compounds of formula Ixe2x80x3: 
or a pharmaceutically acceptable derivative thereof, wherein:
Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and C(O)NHCH[(CH2)1-2OH]R5 are attached to Sp at non-adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6;
Z1 and Z2 are each independently selected from N or CH;
T is a linker group;
U is selected from xe2x80x94NR7xe2x80x94, xe2x80x94NR7COxe2x80x94, xe2x80x94NR7CONR7xe2x80x94, xe2x80x94NR7CO2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CONR7xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94NR7SO2xe2x80x94, xe2x80x94SO2NR7xe2x80x94, xe2x80x94NR7SO2NR7xe2x80x94, or xe2x80x94SO2xe2x80x94;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N (R7)2, OR, or OH;
R3 is selected from R7, R, xe2x80x94(CH2)yCH(R8)R, CN, xe2x80x94(CH2)yCH(R8)CH(R5)21 or xe2x80x94(CH2)yCH(R8)N(R4)2;
each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms;
each R4 is independently selected from R, R7, xe2x80x94COR7, xe2x80x94CO2R, xe2x80x94CON(R7)2xe2x80x94SO2R7, xe2x80x94(CH2)yR5 or xe2x80x94(CH2)yCH(R5)2;
each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring;
R8 is selected from R, (CH2)wOR7, (CH2)wN(R4)2, or (CH2)wSR7; and
each w is independently selected from 0-4.
Examples of suitable Sp groups of formula Ixe2x80x3 include pyrrole (a), imidazole (b), pyrazole (c), triazole (d), oxazole (e), isoxazole (f), 1,3-thiazole (g), 1,2-thiazole (h), furan (i), and thiophene (j), as shown below: 
wherein each of a through j is optionally substituted with R6.
Accordingly, the present invention relates to compounds of formula Ixe2x80x3 wherein Ring A is a pyridine (IIxe2x80x3), pyrimidine (IIIxe2x80x3), or triazine (IVxe2x80x3) ring as shown below: 
or a pharmaceutically acceptable derivative thereof, wherein Sp, TmR1, UnR3, and R5 are as described above.
Preferred TmR1 groups of formula Ixe2x80x3 are hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. Examples of preferred TmR1 groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of formula Ixe2x80x3 are those listed below in Table 1.
Preferred R3 groups of formula Ixe2x80x3 are hydrogen, carbocyclyl, xe2x80x94CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is xe2x80x94CH(R8)R, examples of such groups include xe2x80x94CH(CH2OH)phenyl, xe2x80x94CH(CH2OH)ethyl, xe2x80x94CH(CH2OH)2, xe2x80x94CH(CH2OH)isopropyl, and xe2x80x94CH(CH2OH)CH2cyclopropyl. Preferred Un groups, when present, are xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NR7xe2x80x94, xe2x80x94NHCOxe2x80x94, and xe2x80x94NHCO2xe2x80x94. More preferred UnR3 groups of formula Ixe2x80x3 are those listed in Table 1 below.
Preferred R5 groups of formula Ixe2x80x3 are optionally substituted 6-membered aryl, heteroaryl, and carbocyclic rings, such as phenyl, pyridyl, and cyclohexyl.
Preferred compounds of formula Ixe2x80x3 are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, xe2x80x94CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and
(c) R5 is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.
More preferred compounds of formula Ixe2x80x3 are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, xe2x80x94CH(CH2OH)phenyl, xe2x80x94CH(CH2OH)ethyl, xe2x80x94CH(CH2OH)2, xe2x80x94CH(CH2OH)isopropyl, xe2x80x94CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl or benzyl group;
(b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3; and
(c) R5 is cyclohexyl or an optionally substituted phenyl or pyridylring.
Another preferred embodiment of this invention relates to compounds of formula I0: 
or a pharmaceutically acceptable derivative thereof, wherein:
Sp is a spacer group comprising a 5-membered heteroaromatic ring, wherein Ring A and C(O)NHCH(R8)CH(R5)2 are attached to Sp at non-adjacent positions; and wherein Sp has up to two R6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R6;
Z1 and Z2 are each independently selected from N or CH;
T is a linker group;
U is selected from xe2x80x94NR7xe2x80x94, xe2x80x94NR7COxe2x80x94, xe2x80x94NR7CONR7xe2x80x94, xe2x80x94NR7CO2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CONR7xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94NR7SO2xe2x80x94, xe2x80x94SO2NR7xe2x80x94, xe2x80x94NR7SO2NR7xe2x80x94, or xe2x80x94SO2xe2x80x94;
m and n are each independently selected from zero or one;
R1 is selected from hydrogen, CN, halogen, R, N(R7)2, OR, or OH;
y is 0-6;
R3 is selected from R7, R, xe2x80x94(CH2)yCH(R8)R, CN, xe2x80x94(CH2)yCH(R8)CH(R5)2, or xe2x80x94(CH2)yCH(R8)N(R4)2;
each R4 is independently selected from R, R7, xe2x80x94COR7, xe2x80x94CO2R, xe2x80x94CON(R7)2, xe2x80x94SO2R7, xe2x80x94(CH2)yR5, or xe2x80x94(CH2)yCH(R5)2;
each R is independently selected from an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms;
each R5 is independently selected from R, OR, CO2R, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON (R7)2, SO2R, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R6 is independently selected from R7, F, Cl, (CH2)yN(R7)2, N(R7)2, OR7, SR7, NR7COR7, NR7CON(R7)2, CON(R7)2, SO2R7, NR7SO2R7, COR7, CN, or SO2N(R7)2;
each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring;
R8 is selected from R, (CH2)wOR7, (CH2)wN(R4)2, or (CH2)wSR7; and
each w is independently selected from 0-4.
Examples of suitable Sp groups of formula I0 include pyrrole (a), imidazole (b), pyrazole (c), triazole (d), oxazole (e), isoxazole (f), 1,3-thiazole (g), 1,2-thiazole (h), furan (i), and thiophene (j), as shown below: 
wherein each of a through j is optionally substituted with R6.
Accordingly, the present invention relates to compounds of formula I0 wherein Ring A is a pyridine (II0), pyrimidine (III0), or triazine (IV) ring as shown below: 
or a pharmaceutically acceptable derivative thereof, wherein Sp, TmR1, R5, UnR3, and R8 are as described above.
Preferred R5 groups of formula I0 are R or OR7. Examples of such groups include OH, CH2OH, carbocyclic, or optionally substituted5 or 6-membered aryl or heteroaryl rings, such as phenyl, pyridyl, and cyclohexyl. Preferred R8 groups of formula I0 are R and OR7, wherein R is an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include phenyl, methyl, ethyl, OH, and CH2OH. Preferred substituents on the R5 aryl or heteroaryl ring are halogen, haloalkyl, OR0, and R0.
Preferred TmR1 groups of formula I0 are hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. More preferred TmR1 groups are methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. Most preferred TmR1 groups of formula I0 are those listed in Table 1 below.
Preferred R3 groups of formula I0 are hydrogen, carbocyclyl, xe2x80x94CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is xe2x80x94CH(R8)R, examples of such groups include xe2x80x94CH(CH2OH)phenyl, xe2x80x94CH(CH2OH)ethyl, xe2x80x94CH(CH2OH)2, xe2x80x94CH(CH2OH)isopropyl, and xe2x80x94CH(CH2OH)CH2cyclopropyl. Preferred Un groups, when present, are xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NR7xe2x80x94, xe2x80x94NHCOxe2x80x94, and xe2x80x94NHCO2xe2x80x94. More preferred UnR3 groups of formula I0 are those listed in Table 1 below.
Preferred compounds of formula I0 are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, xe2x80x94CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;
(b) TmR1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and
(c) R5 is R or OR7, wherein R is carbocyclic, or an optionally substituted5 or 6-membered aryl or heteroaryl ring.
More preferred compounds of formula I0 are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, xe2x80x94CH(CH2OH)phenyl, xe2x80x94CH(CH2OH)ethyl, xe2x80x94CH(CH2OH)2, xe2x80x94CH(CH2OH)isopropyl, xe2x80x94CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group;
(b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3; and
(c) R5 is OH, CH2OH, carbocyclic, or an optionally substitutedphenyl or pyridyl ring.
A preferred embodiment relates to compounds of formula III-a: 
or a pharmaceutically acceptable derivative thereof.
Preferred TmR1 groups of formula III-a are hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. Examples of such preferred TmR1 groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of formula III-a are those listed in Table 1 below.
Preferred R3 groups of formula III-a are hydrogen, carbocyclyl, xe2x80x94CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 iS optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is xe2x80x94CH(R8)R, examples of such groups are xe2x80x94CH(CH2OH)phenyl, xe2x80x94CH(CH2OH)ethyl, xe2x80x94CH(CH2OH)2, xe2x80x94CH(CH2OH)isopropyl, and xe2x80x94CH(CH2OH)CH2cyclopropyl. Preferred Un groups, when present, are xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NR7xe2x80x94, xe2x80x94NHCOxe2x80x94, and xe2x80x94NHCO2xe2x80x94. More preferred UnR3 groups of formula III-a are those listed in Table 1 below.
When R2 is R5, preferred R5 groups are pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, and piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl, 4-phenyl-piperazine-1-yl, wherein each group is optionally substituted. When R2 is (CH2)yR5, (CH2)yCH(R5)2, or xe2x80x94N(R4)2, preferred R5 groups are pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl, 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, benzyl, xe2x80x94CH2OH, xe2x80x94(CH2)2OH, and isopropyl, wherein each group is optionally substituted. Preferred substituents on R5 are xe2x80x94OH, pyridyl, piperidinyl, and optionally substituted phenyl. When R2 is xe2x80x94(CH2)yCH(R8)CH(R5)2, preferred R8 groups are R7 and OR7 such as OH and CH2OH. More preferred xe2x80x94QR2 groups are those listed in Table 1 below.
Preferred compounds of formula III-a are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, xe2x80x94CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;
(b) TmR1 is hydrogen, N (R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring;
(c) Q is xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94OC(O)NHxe2x80x94, xe2x80x94C(O)ONHxe2x80x94, or xe2x80x94CONHNHxe2x80x94;
(d) R2 is xe2x80x94NR4(CH2)yN(R4)2, xe2x80x94(CH2)yR5, xe2x80x94(CH2)yCH(R5)2, or xe2x80x94(CH2)yCH(R8)CH(R5)2;
(f) R4 is R, R7, or xe2x80x94(CH2)yCH(R5)2; and
(g) R5 is an optionally substituted group selected from phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl.
More preferred compounds of formula III-a are those having one or more, more preferably more than one, or most preferably all, of the features selected from the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, xe2x80x94CH(CH2OH)phenyl, xe2x80x94CH(CH2OH)ethyl, xe2x80x94CH(CH2OH)2, xe2x80x94CH(CH2OH)isopropyl, xe2x80x94CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl or benzyl group;
(b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3;
(c) Q is xe2x80x94COxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94SO2xe2x80x94, or xe2x80x94SO2NHxe2x80x94;
(d) R2 is xe2x80x94(CH2)yR5, xe2x80x94(CH2)yCH(R5)2, or xe2x80x94(CH2)yCH(R8)CH(R5)2, wherein R8 is OH or CH2OH; and
(e) R5 is xe2x80x94CH2OH, xe2x80x94(CH2)2OH, isopropyl, or an optionally substituted group selected from pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl, 4-phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl, 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, or benzyl.
Preferred compounds of formula III-a include those of formula III-axe2x80x2: 
or a pharmaceutically acceptable derivative thereof.
Preferred R5 groups of formula III-axe2x80x2 are optionally substituted6-membered aryl, heteroaryl, and carbocyclic rings, such as phenyl, pyridyl, and cyclohexyl.
Preferred TmR1 groups of formula III-axe2x80x2 are hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. Preferred TmR1 groups are methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, CH2NHCH3, and those listed in Table 1 below.
Preferred R3 groups of formula III-axe2x80x2 are hydrogen, carbocyclyl, xe2x80x94CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is xe2x80x94CH(R8)R, examples of such groups include xe2x80x94CH(CH2OH)phenyl, xe2x80x94CH(CH2OH)ethyl, xe2x80x94CH(CH2OH)2, xe2x80x94CH(CH2OH)isopropyl, and xe2x80x94CH(CH2OH)CH2cyclopropyl. Preferred Un, groups, when present, are xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NR7 xe2x80x94NHCOxe2x80x94, and xe2x80x94NHCO2xe2x80x94. More preferred UnR3 of formula III-axe2x80x2 are those listed in Table 1 below.
Preferred compounds of formula III-axe2x80x2 are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, xe2x80x94CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and
(c) R5 is an optionally substituted6-membered aryl, heteroaryl, or carbocyclic ring.
More preferred compounds of formula III-axe2x80x2 are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, xe2x80x94CH(CH2OH)phenyl, xe2x80x94CH(CH2OH)ethyl, xe2x80x94CH(CH2OH)2, xe2x80x94CH(CH2OH)isopropyl, xe2x80x94CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl or benzyl group;
(b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3; and
(c) R5 is cyclohexyl or an optionally substituted phenyl or pyridylring.
Preferred compounds of formula III-a are further selected from those of formula III-a0: 
or a pharmaceutically acceptable derivative thereof.
Preferred R5 groups of formula III-a0 are R or OR7. Examples of such groups include OH, CH2OH, or optionally substituted6-membered aryl, heteroaryl, and carbocyclic rings, such as phenyl, pyridyl, and cyclohexyl. Preferred R8 groups of formula III-a0 are R and OR, wherein R is an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include phenyl, methyl, ethyl, OH, and CH2OH.
Preferred TmR1 groups of formula III-a0 are hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring. When R1 is an optionally substituted phenyl or aliphatic group, preferred substituents on the phenyl or aliphatic group are R7, halo, nitro, alkoxy, and amino. Preferred TmR1 groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, NH2, NHCH3, NHAc, NHC (O)NHCH3, and CH2NHCH3. More preferred TmR1 groups of formula III-a0 are those listed in Table 1 below.
Preferred R3 groups of formula III-a0 are hydrogen, carbocyclyl, xe2x80x94CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring. Examples of such groups include methyl, ethyl, propyl, cyclopropyl, cyclohexyl, benzyl, isoxazolyl, tetrahydrofuranyl, and isopropyl. When R3 is optionally substituted phenyl, preferred substituents on the phenyl ring are halogen, alkyl, alkoxy, haloalkyl, Obenzyl, Ophenyl, OCF3, OH, SO2NH2, and methylene dioxy. When R3 is xe2x80x94CH(R8)R, examples of such groups are xe2x80x94CH(CH2OH)phenyl, xe2x80x94CH(CH2OH)ethyl, xe2x80x94CH(CH2OH)2, xe2x80x94CH(CH2OH)isopropyl, and xe2x80x94CH(CH2OH)CH2cyclopropyl. Preferred Un groups, when present, are xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NR7 xe2x80x94NHCOxe2x80x94, and xe2x80x94NHCO2xe2x80x94. More preferred UnR3 groups of formula III-a0 are those listed in Table 1 below.
Preferred compounds of formula III-a0 are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R3 is hydrogen, carbocyclyl, xe2x80x94CH(R8)R, or an optionally substituted group selected from C1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;
(b) TmR1 is hydrogen, N(R4)2, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and
(c) R5 is R or OR7, and R8 is R or OR7.
More preferred compounds of formula III-a0 are those having one or more, more preferably more than one, and most preferably all, of the features selected from the group consisting of:
(a) R3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, xe2x80x94CH(CH2OH)phenyl, xe2x80x94CH(CH2OH)ethyl, xe2x80x94CH(CH2OH)2, xe2x80x94CH(CH2OH)isopropyl, xe2x80x94CH(CH2OH)CH2cyclopropyl, or an optionally substituted phenyl or benzyl group;
(b) TmR1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH2OCH3, CH2OH, OH, NH2, NHCH3, NHAc, NHC(O)NHCH3, or CH2NHCH3; and
(c) R5 is OH, CH2OH, phenyl, pyridyl, or cyclohexyl, and R8 is methyl, ethyl, OH, or CH2OH.
Preferred compounds of formula III-a are set Table 1 below. More preferred compounds in Table 1 are those of formula III-axe2x80x2 or III-ao.
The above formula III-a compounds are those wherein Ring A is a pyrimidine ring and Sp is a pyrrole ring. Inhibitors of formula I wherein Ring A is a pyridine, pyrimidine, or triazine ring having the other Sp rings shown above are otherwise structurally similar to the formula III-a compounds and are represented by the following general formulae II-b through II-j, III-b through III-j, and IV-b through IV-j shown below in Table 2:
The compounds shown above in Table 2 are structurally similar to compounds of formula III-a where the pyrrole ring of formula III-a is replaced by each of the following Sp rings: imidazole (b), pyrazole (c), triazole (d), oxazole (e), isoxazole (f), 1,3-thiazole (g), 1,2-thiazole (h), furan (i), and thiophene (j). Accordingly, preferred QR2, TmR1, and UnR3 groups of the compounds shown above in Table 2 are as described above for the formula III-a compounds.
In another embodiment, this invention provides a pharmaceutically acceptable composition comprising a compound shown above in Table 2 and a pharmaceutically acceptable carrier.
Another aspect of this invention relates to a method of treating or preventing an ERK2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound shown above in Table 2 or a pharmaceutically acceptable composition comprising said compound.
Another aspect of this invention relates to a method of inhibiting ERK2 activity in a patient, which method comprises administering to the patient a compound shown above in Table 2 or a pharmaceutically acceptable composition comprising said compound.
Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound shown above in Table 2 or a pharmaceutically acceptable comprising said compound.
Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound shown above in Table 2 or a pharmaceutically acceptable composition comprising said compound.
Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound shown above in Table 2 or a pharmaceutically acceptable comprising said compound.
One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound shown above in Table 2 or a pharmaceutically acceptable composition comprising said compound. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer""s disease. Another method relates to inhibiting the phosphorylation of xcex2-catenin, which is useful for treating schizophrenia.
Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound shown above in Table 2 or a pharmaceutically acceptable composition comprising said compound.
Another method relates to inhibiting ERK2, Aurora-2, or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with a compound shown above in Table 2, or a pharmaceutically acceptable composition thereof, in an amount effective to inhibit ERK2, Aurora-2, or GSK-3.
Each of the aforementioned methods directed to the inhibition of ERK2, Aurora-2 or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound shown above in Table 2, as described above.
The present compounds may be prepared in general by methods known to those skilled in the art for analogous compounds, as illustrated by the general Schemes I through XII and the synthetic examples shown below. 
Scheme I above shows a general synthetic route that is used for preparing the pyrrol-3-yl compounds of formula III-a of this invention when R2 is an optionally substituted phenyl group or aliphatic group. In step (a), an optionally substituted acid chloride is combined with compound 1, dichloromethane, and aluminum trichloride to form compound 2. In cases where benzoyl acid chlorides are used, a wide variety of substituents on the phenyl ring are amenable to this reaction. Aliphatic acid chlorides are also used in many cases. Examples of suitable R2 groups include, but are not limited to, those set forth in Table 1 above.
The formation of amide 4 is achieved by treating compound 2 with an amine 3 in DMF. When amine 3 is a primary amine, the reaction proceeds at ambient temperature. When amine 3 is a secondary amine, the reaction is heated at 50xc2x0 C. to achieve complete reaction and afford amide 4.
The formation of enamine 5 at step (c) is achieved by treating amide 4 with (Me2N)2xe2x80x94CHOt-Bu at ambient temperature. Alternatively, the reaction to form enamine 5 at step (c) is also achieved by using dimethylformamide-dimethylacetal (DMF-DMA). The reaction using DMF-DMA typically requires elevated temperature to afford enamine 5 whereas using (Me2N)2xe2x80x94OtBu has the advantage of proceeding at ambient temperature to afford the enamine 5 in higher purity.
The formation of the pyrimidine compound 6 at step (d) is achieved by the treatment of enamine 5 with guanidine at elevated temperature. Alternatively, use of a substituted guanidine results in an amino substituent as is illustrated by 8.
As an alternative method, in step (e) intermediate 5 may be cyclized with S-methyl thiourea to form the 2-thiomethylpyrimidine 7 which may in turn be oxidized with m-CPBA to the sulfone. The sulfonyl group may be subsequently displaced by an amine to generate the substituted aminopyrimidine 8.
The compounds of formula III-a synthesized by this method, as exemplified in Table 1, were isolated by preparatory HPLC (reverse phase, 10xe2x86x9290% MeCN in water over 15 minutes). The details of the conditions used for producing these compounds are set forth in the Examples. 
Scheme II above shows a general method for preparing compounds 8 from intermediate 5 and an N-substituted guanidine (9). Intermediate 5 may be prepared according to Scheme I steps (a), (b), and (c) shown above. Compound 5 is treated with N-substituted guanidine (9) and potassium carbonate in dimethylacetamide to form compound 8. This reaction is amenable to a variety of N-substituted guanidines to form compounds of formula III-a. The details of the conditions used for producing these compounds are set forth in the Examples. 
Scheme III above shows a general synthetic route that may be used for preparing the pyrrol-3-yl compounds of formula II-a of this invention. The conversion of intermediate 5 to product 8 may be achieved through steps (c), (d), and (e) according to the method described in JACS, 1957, pp 79. 
Scheme IV above shows a general synthetic route that may be used for preparing the imidazol-4-yl compounds of formula II-b of this invention. The conversion of intermediate 5 to product 8 may be achieved through steps (e), (f), and (g) according to the method described in JACS, 1957, pp 79. 
Scheme V above shows a general synthetic route that may be used for preparing the imidazol-2-yl compounds of formula II-bxe2x80x2 of this invention. The conversion of intermediate 5 to product 8 may be achieved through steps (e), (f), and (g) according to the method described in JACS, 1957, pp 79. 
Scheme VI above shows a general synthetic route that may be used for preparing the pyrazol-3-yl compounds of formula II-c of this invention. The conversion of intermediate 4 to product 7 may be achieved through steps (c), (d), and (e) according to the method described in JACS, 1957, pp 79. 
Scheme VII above shows a general synthetic route that may be used for preparing the oxazol-2-yl compounds of formula II-exe2x80x2 of this invention. The conversion of intermediate 5 to product 8 may be achieved through steps (c), (d), and (e) according to the method described in JACS, 1957, pp 79. 
Scheme VIII above shows a general synthetic route that may be used for preparing the thiazol-2-yl compounds of formula II-gxe2x80x2 of this invention. The conversion of intermediate 5 to product 8 may be achieved through steps (c), (d), and (e) according to the method described in JACS, 1957, pp 79. 
Scheme IX above shows a general synthetic route that may be used for preparing the thiazol-4-yl compounds of formula II-g of this invention. The conversion of intermediate 5 to product 8 may be achieved through steps (e), (f), and (g) according to the method described in JACS, 1957, pp 79. 
Scheme X above shows a general synthetic route that is used for preparing compounds of formula III-a where TmR1 is methoxymethyl or hydroxymethyl. In step (a), 3-methoxypropionyl chloride is combined with compound 1, dichloromethane, and aluminum trichloride to form compound 2.
The formation of amide 4 is achieved by treating compound 2 with an amine 3 in DMF. When amine 3 is a primary amine, the reaction proceeds at ambient temperature. When amine 3 was a secondary amine, the reaction is heated at 50xc2x0 C. to achieve complete reaction and afford amide 4. The formation of enamine 5 at step (c) is achieved by treating amide 4 with (Me2N)2xe2x80x94CHOt-Bu at ambient temperature.
The formation of the pyrimidine compound 6 at step (d) is achieved by the treatment of enamine 5 with a guanidine at elevated temperature. Alternatively, use of a substituted guanidine results in an amino substituent.
To form compounds where TmR1 is hydroxymethyl, intermediate 6 may be treated with BBr3 in dichloromethane to form compounds 7. One of skill in the art would recognize that the hydroxymethyl group of compound 7 could be further derivatized to form a variety of compounds of formula III-a. The details of the conditions used for producing these compounds are set forth in the Examples. 
Scheme XI above shows a general method for preparing the triazine compounds of formula IV-a. Step (a) is performed in the manner described at Scheme I, step (b) above. Step (b) is performed in the manner described at Scheme I, step (a) above. The formation of the triazine ring at step (c) may be performed according to the methods described by Hirsch, J.; Petrakova, E.; Feather, M. S.; J Carbohydr Chem [JCACDM] 1995, 14 (8), 1179-1186. Alternatively, step (c) may be performed according to the methods described by Siddiqui, A. U.; Satyanarayana, Y.; Rao, U. M.; Siddiqui, A. H.; J Chem Res, Synop [JRPSDC] 1995 (2), 43. 
Using the preparation of compound III-a-226 to illustrate, Scheme XII above shows a general synthetic route that is used for preparing compounds of formula III-a where Un is NR7. The formation of the pyrimidine compound III-a-226 at step (a) is achieved by the treatment of enamine 5 with a guanidine 6 at elevated temperature. Alternatively, use of a substituted amino guanidine results in an hydrazyno substituent.
In another embodiment, this invention provides a pharmaceutically acceptable composition comprising a compound of formula Ixe2x80x2, Ixe2x80x3, Io, III-a, III-axe2x80x2, or III-ao, and a pharmaceutically acceptable carrier.
Another aspect of this invention relates to a method of treating or preventing an ERK2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of compound of formula Ixe2x80x2, Ixe2x80x3, Io, III-a, III-axe2x80x2, or III-ao, or a pharmaceutically acceptable composition comprising said compound.
Another aspect of this invention relates to a method of inhibiting ERK2 activity in a patient, which method comprises administering to the patient compound of formula Ixe2x80x2, Ixe2x80x3, Io, III-a, III-axe2x80x2, or III-ao, or a pharmaceutically acceptable composition comprising said compound.
Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Ixe2x80x2, Ixe2x80x3, Io, III-a, III-axe2x80x2, or III-ao, or a pharmaceutically acceptable composition comprising said compound.
Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula Ixe2x80x2, Ixe2x80x3, Io, III-a, III-axe2x80x2, or III-ao, or a pharmaceutically acceptable composition comprising said compound.
Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula Ixe2x80x2, Ixe2x80x3, Io, III-a, III-axe2x80x2, or III-ao, or a pharmaceutically acceptable composition comprising said compound.
One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula Ixe2x80x2, Ixe2x80x3, Io, III-a, III-axe2x80x2, or III-ao, or a pharmaceutically acceptable composition comprising said compound. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer""s disease. Another method relates to inhibiting the phosphorylation of xcex2-catenin, which is useful for treating schizophrenia.
Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula Ixe2x80x2, Ixe2x80x3, Io, III-a, III-axe2x80x2, or III-ao, or a pharmaceutically acceptable composition comprising said compound.
Another aspect of this invention relates to a method of treating or preventing a CDK-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Ixe2x80x2, Ixe2x80x3, Io, III-a, III-axe2x80x2, or III-ao, or a pharmaceutically acceptable composition comprising said compound.
The term xe2x80x9cCDK-2-mediated conditionxe2x80x9d or xe2x80x9cdiseasexe2x80x9d, as used herein, means any disease or other deleterious condition in which CDK-2 is known to play a role. The term xe2x80x9cCDK-2-mediated conditionxe2x80x9d or xe2x80x9cdiseasexe2x80x9d also means those diseases or conditions that are alleviated by treatment with a CDK-2 inhibitor. Such conditions include, without limitation, cancer, Alzheimer""s disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis. See Fischer, P. M. and Lane, D. P., Current Medicinal Chemistry, 7, 1213-1245 (2000); Mani, S., Wang, C., Wu, K., Francis, R. and Pestell, R., Exp. Opin. Invest. Drugs, 9, 1849 (2000); Fry, D. W. and Garrett, M. D., Current Opinion in Oncologic, Endocrine and Metabolic Investigational Drugs, 2, 40-59 (2000).
Another aspect of this invention relates to a method of treating or preventing a Lck-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Ixe2x80x2, Ixe2x80x3, Io, III-a, III-axe2x80x2, or III-ao, or a pharmaceutically acceptable composition comprising said compound.
The terms xe2x80x9cLck-mediated diseasexe2x80x9d or xe2x80x9cLck-mediated conditionxe2x80x9d, as used herein, mean any disease state or other deleterious condition in which Lck is known to play a role. The terms xe2x80x9cLck-mediated diseasexe2x80x9d or xe2x80x9cLck-mediated conditionxe2x80x9d also mean those diseases or conditions that are alleviated by treatment with an Lck inhibitor. Lck-mediated diseases or conditions include, but are not limited to, autoimmune diseases such as transplant rejection, allergies, rheumatoid arthritis, and leukemia. The association of Lck with various diseases has been described [Molina et al., Nature, 357, 161 (1992)].
Another aspect of this invention relates to a method of treating or preventing an AKT3-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Ixe2x80x2, Ixe2x80x3, Io, III-a, III-axe2x80x2, or III-ao, or a pharmaceutically acceptable composition comprising said compound.
The terms xe2x80x9cAKT3-mediated diseasexe2x80x9d or xe2x80x9cAKT3-mediated conditionxe2x80x9d, as used herein, mean any disease state or other deleterious condition in which AKT3 is known to play a role. The terms xe2x80x9cAKT3-mediated diseasexe2x80x9d or xe2x80x9cAKT3-mediated conditionxe2x80x9d also mean those diseases or conditions that are alleviated by treatment with an AKT inhibitor. AKT3-mediated diseases or conditions include, but are not limited to, proliferative disorders, cancer, and neurodegenerative disorders. The association of AKT3 with various diseases has been described [Zang, Q. Y., et al, Oncogene, 19 (2000)] and [Kazuhiko, N., et al, The Journal of Neuroscience, 20 (2000)].
Another method relates to inhibiting ERK2, Aurora-2, CDK-2, Lck, AKT3, or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with a compound of formula Ixe2x80x2, Ixe2x80x3, Io, III-a, III-axe2x80x2, or III-ao, or a pharmaceutically acceptable composition comprising said compound, in an amount effective to inhibit ERK2, Aurora-2, CDK-2, Lck, AKT3, or GSK-3.
Each of the aforementioned methods directed to the inhibition of ERK2, Aurora-2, CDK-2, Lck, AKT3, or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula Ixe2x80x2, Ixe2x80x3, Io, III-a, III-axe2x80x2, or III-ao, as described above. More preferably, each of the aforementioned methods is carried out with a preferred compound of formula Ixe2x80x2, Ixe2x80x3, Io, III-axe2x80x2, or III-ao, and most preferably with a compound of formula Ixe2x80x3, Io, III-axe2x80x2, or III-ao.